Organ transplantation is extensively used for organs such as the heart, the lung, the pancreas, the intestine (colon) and, in particular, the kidney and the liver. The growing demand of organs and the scarcity of donours have led to a growing waiting list and a greater need to use organs from sub-optimal donours.
Organs obtained for transplantation must be stored and transported from one hospital to another. Time is needed to test the histocompatibility between donour and recipient, and to prepare the recipient patient. The time period during which organs and tissues may be maintained outside the body varies, depending on the organ, the donour's age and health condition, the preservation method and the temperature.
Currently, the standard technique used in clinical practise to prolong the viability of donated organs is cold storage or cold preservation, by means of special preservation solutions. These solutions are used in a first stage, prior to the extraction, for a perfusion (flushing) of the organ designed to remove and replace the donour's blood, whilst cooling it to 4° C. In a second stage, the cold preservation solutions are used to store and preserve the extracted organ, also under hypothermia (about 4° C.), until transplantation. The purpose of cold preservation is to preserve the organ by means of a suppression of metabolism and, in the second place, to prevent and minimise the alterations that cold ischaemia might cause.
Maathuis et al. (Transplantation, 2007; 83: 1289-1298) provide a recent review of cold preservation solutions which discloses the general requirements, as well as the composition and the properties of a large number thereof, such as the Euro-Collins solution (EC). Marshall's hypertonic citrate solution (HOC), sucrose phosphate buffer, the University of Wisconsin solution (UW), the histidine-tryptophan-ketoglutarate (HTK) solution, the Celsior solution (CEL), the Institut Georges López solution (IGL-1). There are comparative studies on the efficacy of some of these solutions on the preservation of the kidney (Ahmad et al. Kidney International 2006; 69: 884-893), the heart (Michel et al. J. Heart Lung Transplant 2002; 21: 1030-1039), the liver (El-Wahsh M. Hepatobiliary Pancreat Dis Int 2007; 6: 12-16) and the intestine (Wei et al. Gastroenterology 2007; 13:3n84-3091),
The most commonly used cold preservation solutions are the University of Wisconsin solution, in particular for the liver and the kidney; the Celsior solution for heart preservation; and Euro-Collins or PERFADEX™ for lung preservation. In the case of perfusion machines, these have been modified, for example to UW-gluconate (Belzer MPS).
U.S. Pat. No. 4,798,824 discloses a cold preservation solution that comprises gluconate and hydroxyethyl starch. U.S. Pat. No. 4,879,283 discloses the University of Wisconsin solution (UW or Belzer solution), which comprises the following differential components: lactobionate and raffinose, as impermeating agents designed to reduce cellular swelling; and hydroxyethyl starch, in order to prevent edema.
However, cold preservation with the current preservation solutions has significant limitations. The tissue damage and the inflammatory response caused by cold preservation may increase immunogenicity and initiate rejection of the organ. Thus, for example, in experimental models of kidney transplantation with rejection, cold ischaemia contributed to an increase in the mortality rate due to kidney failure and an accelerated acute rejection (Salahudeen A K. Am J Physiol Renal Physiol. 2004; 287: F181-F187; Herrero-Fresneda et al. Transplant Proc. 2005; 37: 3712-3715).
Cold ischaemia is related to alterations of osmoregulation, energy and the aerobic metabolism. A reduction in Na—K-ATPase activity and ATP levels allows for an intracellular accumulation of sodium and water, thereby causing cellular swelling. Likewise, the lactic acid produced by glucose metabolism leads to lysosomal instability and alteration of the mitochondrial function, causing swelling, activation of the mitochondrial apoptotic pathway and production of free radicals.
On the other hand, once the transplantation has been performed, a new damage is added, caused by re-perfusion of the organ, which is possibly more sensitive due to the cold ischaemia whereto it has been subjected. The following are involved in this damage process: an increase in reactive oxygen free radicals, in the inflammatory response and the cytosolic calcium, as well as an activation of proteolytic enzymes, for example, caspases.
Consequently, there is a need in the state of the art to provide an adequate cold organ preservation composition that makes it possible to reduce the damages associated with cold ischaemia and the post-transplantation reperfusion of cold-preserved organs.